Various patents and other publications are referenced herein. The contents of each of these patents and publications are incorporated by reference herein, in their entireties. The entire contents of commonly-owned co-pending U.S. application Ser. No. 10/440,583, filed May 19, 2003, are incorporated by reference herein.
Aging-related cataract results from gradual opacification of the crystalline lens of the eye. This disease is presently treated by surgical removal and replacement of the affected lens. It is believed that once begun, cataract development proceeds via one or more common pathways that culminate in damage to lens fibers. This condition progresses slowly and occurs predominantly in the elderly. Alternatively, cataract may form because of surgical, radiation or drug treatment of a patient, e.g. after surgery of an eye to repair retinal damage (vitrectomy) or to reduce elevated intraocular pressure; x-irradiation of a tumor; or steroid drug treatment. A significant retardation of the rate of cataract development in such patients may eliminate the need for many surgical cataract extractions. This reduction would provide tremendous benefits both to individual patients and to the public health system.
A less serious but more pervasive condition of the ocular lens is presbyopia. The lens is enveloped by a tough collagen capsule that is thought to impart elasticity to the lens, enabling it to focus at different distances through ciliary muscle-controlled changes of curvature. As the lens ages, it increases in volume and hence progressively loses its elasticity, which diminishes an individual's ability to focus on near objects. This condition is known as presbyopia, and occurs in a large percentage of the aging population.
In addition to cataract and presbyopia, the eye can experience numerous diseases and other deleterious conditions that affect its ability to function normally. Many such conditions can be found in the interior and most particularly at the rear of the eye, where lies the optic nerve and the retina, seven layers of alternating cells and processes that convert a light signal into a neural signal. Diseases and degenerative conditions of the optic nerve and retina are the leading causes of blindness throughout the world.
A significant degenerative condition of the retina is macular degeneration, also referred to as age-related macular degeneration (AMD). AMD is the most common cause of vision loss in the United States in those 50 or older, and its prevalence increases with age. AMD is classified as either wet (neovascular) or dry (non-neovascular). The dry form of the disease is most common. It occurs when the central retina has become distorted, pigmented, or most commonly, thinned. The wet form of the disease is responsible for most severe loss of vision. The wet form of macular degeneration is usually associated with aging, but other diseases that can cause wet macular degeneration include severe myopia and some intraocular infections like histoplasmosis, which may be exacerbated in individuals with AIDS. A variety of elements may contribute to macular degeneration, including genetic makeup, age, nutrition, smoking and exposure to sunlight.
Retinopathy associated with diabetes is a leading cause of blindness in type 1 diabetes, and is also common in type 2 diabetes. The degree of retinopathy depends on the duration of the diabetes, and generally begins to occur ten or more years after onset of diabetes. Diabetic retinopathy may be classified as (1) non-proliferative or background retinopathy, characterized by increased capillary permeability, edema, hemorrhage, microaneurysms, and exudates, or 2) proliferative retinopathy, characterized by neovascularization extending from the retina to the vitreous, scarring, fibrous tissue formation, and potential for retinal detachment. Diabetic retinopathy is believed to be caused, at least in part, by the development of glycosylated proteins due to high blood glucose. Glycosylated proteins generate free radicals, resulting in oxidative tissue damage and depletion of cellular reactive oxygen species (ROS) scavengers, such as glutathione.
Several other less common, but nonetheless debilitating retinopathies include choroidal neovascular membrane (CNVM), cystoid macular edema (CME, also referred to as macular edema or macular swelling), epi-retinal membrane (ERM) (macular pucker) and macular hole. In CNVM, abnormal blood vessels stemming from the choroid grow up through the retinal layers. The fragile new vessels break easily, causing blood and fluid to pool within the layers of the retina. In CME, which can occur as a result of disease, injury or surgery, fluid collects within the layers of the macula, causing blurred, distorted central vision. ERM (macular pucker) is a cellophane-like membrane that forms over the macula, affecting the central vision by causing blur and distortion. As it progresses, the traction of the membrane on the macula may cause swelling. ERM is seen most often in people over 75 years of age. Its etiology is unknown, but may be associated with diabetic retinopathy, posterior vitreous detachment, retinal detachment or trauma, among other conditions.
Another disease of the interior of the eye is uveitis, or inflammation of the uveal tract. The uveal tract (uvea) is composed of the iris, ciliary body, and choroid. The uvea is the intermediate of the three coats of the eyeball, sandwiched between the sclera and the retina in its posterior (choroid) portion. Uveitis may be caused by trauma, infection or surgery, and can affect any age group. Uveitis is classified anatomically as anterior, intermediate, posterior, or diffuse. Anterior uveitis affects the anterior portion of the eye, including the iris. Intermediate uveitis, also called peripheral uveitis, is centered in the area immediately behind the iris and lens in the region of the ciliary body. Posterior uveitis may also constitute a form of retinitis, or it may affect the choroids or the optic nerve. Diffuse uveitis involves all parts of the eye.
Glaucoma is made up of a collection of eye diseases that cause vision loss by damage to the optic nerve. Elevated intraocular pressure (IOP) due to inadequate ocular drainage is a primary cause of glaucoma. Glaucoma can develop as the eye ages, or it can occur as the result of an eye injury, inflammation, tumor or in advanced cases of cataract or diabetes. It can also be caused by certain drugs such as steroids. Further, glaucoma can develop in the absence of elevated IOP. This form of glaucoma has been associated with inheritance (i.e., family history of normal-tension glaucoma) Japanese ancestry, as well as systemic heart disease, such as irregular heartbeat.
The eye produces about one teaspoon of aqueous humor daily. Normally, this fluid escapes from the eye through a spongy mesh of connective tissue called the trabecular meshwork at the same rate at which it is produced. Free radicals and other reactive oxygen species (ROS) cause gradual damage to the trabecular meshwork over a period of time. As a result, the trabecular meshwork becomes partially blocked, outflow facility decreases and the IOP builds up as more aqueous humor is formed. Though the IOP does not rise high enough to cause any noticeable symptoms initially, when pressure remains elevated or continues to rise, fibers in the optic nerve are compressed and destroyed, leading to a gradual loss of vision over a period of years. Izzotti et al. provide convincing evidence linking oxidative DNA damage in a small but critical tissue structure in the outflow system to glaucoma (Izzotti A, Sacca S C, Cartiglia C, De Flora S. Oxidative deoxyribonucleic damage in the eyes of glaucoma patients. Am J. Med. 2003; 114:638-646). They observed a more than threefold increase in the amount of 8-oxo-deoxyguanosine (8-OH-dG) in the trabecular meshwork tissue of glaucoma patients. The increased oxidative DNA damage correlated further with clinical parameters, such as intraocular pressure indexes and visual field loss.
The primary features of the optic neuropathy in glaucoma include characteristic changes in the optic nerve head, a decrease in number of surviving retinal ganglion cells, and loss of vision. It has been proposed that a cascade of events links degeneration of the optic nerve head with the slow death of retinal ganglion cells observed in the disease, and that this cascade of events can be slowed or prevented through the use of neuroprotective agents (Osborne et al., 2003, Eur. J. Ophthalmol. 13 ( Supp 3): S19-S26), of which antioxidants and free radical scavengers are an important class (Hartwick, 2001, Optometry and Vision Science 78: 85-94).
The eye's outermost layer, the cornea, controls and focuses the entry of light into the eye. The cornea must remain transparent to refract light properly. The cornea also helps to shield the rest of the eye from germs, dust, and other harmful matter, and, significantly, it serves as a filter to screen out some of the most damaging ultraviolet (UV) wavelengths in sunlight. Without this protection, the lens and the retina would be highly susceptible to injury from UV radiation.
The cornea and surrounding conjunctiva are also subject to a variety of deleterious conditions that can impair vision. These include inflammatory responses, such as those resulting from allergic reaction, infection or trauma, and a variety of dystrophies (conditions in which one or more parts of the cornea lose their normal clarity due to a buildup of cloudy material), such as Fuchs' dystrophy, keratoconus, lattice dystrophy, and map-dot-fingerprint dystrophy, to name a few, as well as other disorders (e.g., dry eye syndrome).
Ocular surface and lacrimal gland inflammation has been identified in dry eye that plays a role in the pathogenesis of ocular surface epithelial disease, termed keratoconjunctivitis sicca. Both oxidative tissue damage and polymorphonuclear leukocytes indicating an oxidative potential occur in the tear film of patients suffering from dry eyes. These reactions lead to severe damage of the involved tissue. Free radicals and inflammation may be involved in the pathogenesis or in the self-propagation of the disease. (Augustin, A. J. et al., “Oxidative reactions in the tear fluid of patients suffering from dry eyes” Graefe's Arch. Clin.l Exp.l Ophthalmol. 1995, 11:694-698).
Blepharitis is an inflammation of the eyelids. Blepharoconjunctivitis is an inflammation of the eyelids and the conjunctiva of the eye. Both conditions are associated with the condition known as ocular rosacea, though other causes can be present. Blepharitis is an abnormal condition wherein the tears produced contain an excess of lipids (the oily ingredient in natural tears) and, in some cases, contain an irritating oil as well. As explained hereinafter, this oil ingredient serves to prevent evaporation of the aqueous layer that wets the corneal epithelium of the eye and helps spread the aqueous layer over the normally aqueous-resistant cornea during a blink. If excess oil is present, the lipid layer will tend to adhere to the cornea itself. If the eye is unable to clear this oil from the surface of the cornea, a “dry” area occurs on the cornea since the aqueous layer is unable to hydrate this area.
Rosacea is a disease of the skin (acne rosacea) and eyes (ocular rosacea) of unknown etiology and a variety of manifestations. The clinical and pathological features of the eye disease are nonspecific, and the disease is widely underdiagnosed by ophthalmologists.
Retinal phototoxicity is induced by exposure of the eye to retinal illumination from an operating microscope positioned for temporal approach eye surgery or from lasers used by the military. These light sources have the potential for light-induced injury to the fovea (M. A. Pavilack and R. D. Brod “Site of Potential Operating Microscope Light-induced Phototoxicity on the Human Retina during Temporal Approach Eye Surgery” Ophthalmol. 2001, 108(2): 381-385; H. F. McDonald and M. J. Harris “Operating microscope-induced retinal phototoxicity during pars plana vitrectomy” Arch. Ophthalmol. 1988 106:521-523; Harris M. D. et al. “Laser eye injuries in military occupations” Aviat. Space Environ. Med. 2003, 74(9): 947-952). Damage may also occur upon treatment of ablated surface of corneas after excimer laser phototherapy (Seiji Hayashi et al. “Oxygen free radical damage in the cornea after excimer laser therapy” Br. J. Ophthalmol. 1997, 81:141-144).
Certain corneal disorders are not correctable and may be remedied only by corneal transplant, while others may be corrected by phototherapeutic keratectomy (PTK), i.e., eximer laser surgery, the process of which is also known to cause an inflammatory response, causing corneal hazing or areas of corneal opacification.
The skin around the eyes is also subject to disease and disorders. In particular, rosacea of the eyelids and blepharitis are disorders which can be severe. Ocular rosacea is a common and potentially blinding eye disorder with an uncertain etiology (Stone D. U. and J. Chodosh, 2004 Curr. Opin. Ophthalmol. 15(6):499-502). Blepharitis of the eyes may be Staphylococcal blepharitis, seborrheic blepharitis, mixed forms of these, or the most severe form, ulcerative blepharitis.
Oxidative stress has been implicated in the development or acceleration of numerous ocular diseases or disorders, including AMD and the various retinopathies described above (see, e.g., Ambati et al., 2003, Survey of Ophthalmology 48: 257-293; Berra et al., 2002, Arch. Gerontol. Geriatrics 34: 371-377), as well as uveitis (e.g., Zamir et al., 1999, Free Rad. Biol. Med. 27: 7-15), cataract (e.g., M. Lou, 2003, Prog. Retinal & Eye Res. 22: 657-682), glaucoma (e.g., Babizhayev & Bunin, 2002, Curr. Op. Ophthalmol. 13: 61-67), corneal and conjuctival inflammations, various corneal dystrophies, post-surgical or UV-associated corneal damage (e.g., Cejkova et al., 2001, Histol. Histopathol. 16: 523-533; Kasetsuwan et al., 1999, Arch. Ophthalmol. 117: 649-652), and presbyopia (Moffat et al., 1999, Exp. Eye Res. 69: 663-669). For this reason, agents with anti-oxidative properties have been investigated as potential therapeutic agents for the treatment of such disorders. Many investigations have focused on the biochemical pathways that generate reducing power in cells, for example, glutathione synthesis and cycling. Enzymes, such as superoxide dismutase, that reduce activated oxygen species have also been studied to determine whether they diminish cellular oxidative stress. Compounds for inhibiting lipid oxidation in cell membranes by direct radical scavenging have also been considered to be promising therapeutic interventions.
Nitroxides are stable free radicals that are reducible to their corresponding hydroxylamines. These compounds are of interest because of their radical scavenging properties, mimicking the activity of superoxide dismutase and exerting an anti-inflammatory effect in various animal models of oxidative damage and inflammation. Due to their comparative lack of toxicity, hydroxylamines are preferable to nitroxides as therapeutic agents.
It has been known to provide certain hydroxylamine compositions for the prevention or retardation of cataracts. U.S. Pat. No. 6,001,853, in the name of Zigler, et al., the content of which is incorporated herein by reference, reflects work performed at the National Institutes of Health of the United States. Zigler et al. identified a class of hydroxylamines which, when administered to the eye of a test animal, ameliorated cataract genesis or development. Such administration was necessarily via injection for physico-chemical reasons. While Zigler et al. disclosed that it would be clinically convenient to deliver tempol-H by liquid eye drops, no working example was reported, Zigler's hydroxylamines being actually administered by subconjunctival injections. Zigler's materials were also accompanied by the co-administration of a reducing agent, either via injection, systemically or otherwise. It is believed that subsequent work at the National Institutes of Health was directed to the identification of effective hydroxylamines that could be administered topically, however those efforts were not successful.
Accordingly, it has been the object of intense research activity to identify compounds and compositions containing them that can ameliorate cataract formation and development in the eyes of patients, without the need for unpleasant, inconvenient and potentially dangerous intraocular injections. In particular, a long-felt need has existed, which has not been fulfilled, for such compounds and compositions which can be administered via topical application, especially via eye drops.